Reliably modulating or controlling the foreign body response (FBR) elicited by implanted biomaterials has proven difficult in many implant sites and device designs. The pathology of this reaction, noted by hallmark unresolved inflammatory markers, thick fibrous encapsulation and recruitment of acute inflammatory and eventually immune cells in soft tissues, reduces device functionality and pre-disposes the site to infection risk. Much recent research activity has sought to address the FBR problem using biomimetic and natural materials with some notable successes. However, these materials strategies alone are incapable of overcoming other requisite aspects of device in vivo performance, including tissue specific properties: tensile strength, porosity and micro-architecture, and custom defect-specific device morphologies (macrostructure). These challenges and observations frame our overall working hypothesis that implanted biomaterial scaffolds integrated with microstructure, natural materials chemistry, and mechanical properties of natural soft tissue are superior in their cell and tissue healing responses, exhibiting a reduced foreign body response, when compared to classic biomaterials designed with only one of these features. Tasks to directly address this hypothesis are organized around the following specific aims: (1) Demonstrate that matrix protein-modified porous scaffolds fabricated with specific macro- and micro-structural control reduce the foreign body response based on cell recruitment, cytokine profiles, fibrous capsule thickness, vascularity, degradation, and numbers of resident macrophages/foreign body giant cells in a murine subcutaneous pocket model. (1A) Distinguish in vivo performance of matrix protein scaffolds using these biological metrics compared to analogous conventional degradable polyurethane controls; (1B) Distinguish in vivo performance of matrix protein-coated porous non-degradable polyurethane scaffolds using these biological metrics compared to analogous unmodified polyurethane controls; (2) Assess how altering protein/glycosaminoglycan (GAG) ratios, specific protein charge density, and matrix crosslinking alter the FBR as demonstrated by cytokine profiles, fibrous capsule thickness, vascularity, degradation, and numbers of resident macrophages/foreign body giant cells in a murine subcutaneous pocket model; (3) Distinguish how adipose-derived stem cell (ASC) wound site pre-seeding and device ASC seeding alter the FBR as assessed by cell populations, cytokine profiles, fibrous capsule thickness, vascularity, degradation, and numbers of resident macrophages/foreign body giant cells in a murine subcutaneous pocket model. Integrated together, these device-based modifications are proposed to substantially improve local device-associated healing and mitigate adverse events surrounding the host FBR. PUBLIC HEALTH RELEVANCE: Biocompatible, architecturally complex, 3D, medical implants will benefit millions of patients. However, the foreign body response (FBR), a common barrier to successful device integration, is not well understood in the literature. We propose to address this unresolved FBR issue by 1) comparing the FBR of our novel proteinaceous scaffolds to that from commonly employed degradable biomaterials, 2) comparing the FBR of protein-coated versus non-coated non-degradable materials, 3) modifying the proteinaceous scaffold composition, surface charge, and crosslinking chemistry, and 4) seeding these scaffolds with immunomodulatory adipocyte stem cells (ASCs) to further mitigate the FBR to implanted materials. Rapid translation of the proposed extracellular matrix-derived scaffolds and protein coatings for clinical use as an alternative to the current array of biomaterials and tissue engineering scaffolds is desired.